ClinVar Miner

Submissions for variant NM_017849.4(TMEM127):c.281G>A (p.Arg94Gln)

gnomAD frequency: 0.00003  dbSNP: rs746831347
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000308137 SCV000432547 likely benign Pheochromocytoma 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV000639359 SCV000760931 uncertain significance Hereditary pheochromocytoma-paraganglioma 2022-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 94 of the TMEM127 protein (p.Arg94Gln). This variant is present in population databases (rs746831347, gnomAD 0.006%). This missense change has been observed in individual(s) with abdominal paraganglioma (PMID: 31666924). ClinVar contains an entry for this variant (Variation ID: 337506). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV000308137 SCV000895511 uncertain significance Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016682 SCV001177663 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-07 criteria provided, single submitter clinical testing The p.R94Q variant (also known as c.281G>A), located in coding exon 2 of the TMEM127 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in a Saudi proband with abdominal paraganglioma (Albattal S et al. Oncotarget 2019 Oct;10(57):5919-5931) and also in a patient (also Saudi) undergoing multigene testing for breast cancer (Alanazi M et al. Saudi J Biol Sci 2020 Oct;27(10):2651-2659). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV002469134 SCV002011572 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
GeneDx RCV002469134 SCV002765255 uncertain significance not provided 2022-12-08 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with an abdominal paraganglioma without a family history of PCC/PGL (Alanazi et al., 2020); This variant is associated with the following publications: (PMID: 21156949, 32994724, 31666924)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002469134 SCV004221323 uncertain significance not provided 2023-02-13 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMID: 32994724 (2020)), and abdominal paraganglioma (PMID: 31666924 (2019)). The frequency of this variant in the general population, 0.000054 (7/129096 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Baylor Genetics RCV000308137 SCV005054303 uncertain significance Pheochromocytoma 2024-02-02 criteria provided, single submitter clinical testing

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